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Wednesday, June 22, 2016

CORRUPTION OF CLINICAL TRIALS REPORTS: A PROPOSAL

CORRUPTION OF CLINICAL TRIALS REPORTS:

A PROPOSAL

There is a disconnection between the FDA’s drug approval
process and the reports we see in medical journals. Pharmaceutical corporations
exploit this gap through adulterated, self-serving analyses, and the FDA sits
on its hands. I suggest we need a new mechanism to fix the problem – by independent
analyses of clinical trials data.

When they analyze and publish their clinical trials in
medical journals, pharmaceutical corporations have free rein to shape the
analyses. The FDA conducts independent analyses of the data submitted by the
corporations, and it may deny or delay approval. But the FDA does not challenge
the reports that flood our medical journals, both before and after FDA approval.
It is no secret that these publications are routinely biased for marketing
effect, but the FDA averts its gaze. That failure of the FDA – a posture known
as enforcement discretion – has been well documented. The
question is why? At the same time, exposing the biases has been difficult for
outsiders because the data are considered proprietary secrets.

A Case Study

Now, a detailed example of deliberate corporate bias has finally
been documented, through materials released in litigation. This exposé was
reported by Drs. Jon Jureidini, Jay Amsterdam, and Leemon McHenry. Their
findings were recently published, and their article is freely
available on-line. This example concerned a clinical trial of an
antidepressant drug in children and adolescents. The drug, citalopram, was
already approved for use in adults, and its off-label use in children would spread
if there was published supportive evidence. An Investigational New Drug (IND)
protocol and plan of analysis were filed by Forest Laboratories with the FDA in
1999. The trial was completed in 2002, and the results were published
in American Journal of Psychiatry in 2004 – but the FDA did not accept the
results as sufficient to approve this drug for use in children or adolescent
patients. By that time the patent on citalopram had expired and Forest
Laboratories introduced a virtual twin drug, escitalopram (single active enantiomer).
That more expensive version of citalopram was heavily promoted, and it was
approved in 2009 for use in children, but even then the FDA specifically noted
that safety and efficacy were not established in children under age 12. Since
then, new
analyses suggest that most antidepressant drugs have little evidence of
efficacy even in older children.

Tricks of the Trade

In service of a positive report, the statistical analyses
performed by Forest Laboratories deviated from the IND plan of analysis, and
negative results were edited out. The biases now documented by Dr. Jureidini
and his colleagues for that 2004 sponsored report
in American Journal of Psychiatry included:

·Inflating the main
measure of the drug's effect by reporting an incorrect and clearly exaggerated
effect size. On being challenged, the authors
later explained their misinformed
computation without actually acknowledging the error.

·Failure to report
secondary measures of response because they were negative. Those measures had
been stipulated in the IND protocol to serve as cross-checks on the main result.
These negative findings were airbrushed out of the publication by corporate
marketing.

·Unplanned, new
secondary measures of response were inserted ex post facto because they were positive (that is a real no-no).

·Violations of the
IND protocol were not reported and were then fudged (patients who had properly
been excluded per protocol were put back in for analysis, which made a
nonsignificant primary outcome analysis turn positive).

·Adverse events were
analyzed and summarized in a misleading way.

·The finding that
the drug had no effect on depression in children under age 12 was not reported,
even though an age-effect interaction analysis had been specifically projected
in the IND protocol. This strategic omission left the impression that off label
use of citalopram in younger children could be clinically reasonable.

·The corporation knew that another, unpublished,
trial in children, conducted by their European partner Lundbeck was negative,
and that it raised concerns about suicide risk, but that information was
withheld. The authors later were challenged
in the journal about this concealment. Their response
was utterly disingenuous.

·The published article failed to acknowledge that
it was authored by a non-medical ghostwriter, who took direction from marketing
executives – the 2004 publication was a marketing product purporting to be an
objective scientific report.

·Academic authors were recruited only after the
manuscript was written, reviewed, and approved in-house – these nominal
academic authors were signed on to front for the corporate narrative.

·The perfunctory role of the academic (ahem) authors
is clear from the fact that they failed to recognize the wildly inflated effect
size claimed for the drug – something that was instantly obvious to several
groups of competent
readers.

The Payoff

These changes created the appearance of a positive result,
and the publication drew wide attention. According to Thomson Reuters Web of
Science, it has been cited over 160 times, placing it in the top 5% of cited
articles in clinical medicine from 2004. This early publication gave plausible
justification for off-label use of citalopram/escitalopram in children, even
with FDA approval having been denied, and even though the trial was actually
negative. The FDA has
reported that between 2005 and 2010 well over 750,000 patients up to age 17
received escitalopram, including almost 160,000 under age 12. Thus, the sleight
of hand about failure to show even fudged efficacy in younger children is
especially deplorable. Internal memoranda reproduced in the exposé by Dr.
Jureidini and his colleagues give a clear picture of the corporate manipulation
of the scientific publication process. Now we know – in black and white – just
how bad the bias can be. This kind of data manipulation, with ad hoc cherry picking and moving of
goalposts, is unacceptable, but it is entrenched. Indeed, it is business
as usual – and the FDA looks
away.

A Specific Proposal

Our primary defense against such perversions of scientific
reporting is fidelity to the registered IND protocol and plan of statistical analysis.
The solution is not hard to see: We need independent analyses of clinical
trials because we cannot trust the corporate analyses. In effect, we need something
like the Underwriters Laboratory to verify the statistical analyses of clinical
trials. Nobody takes the manufacturing corporation’s word for it concerning the
safety and performance of X-ray machines or cardiac defibrillators. Why treat the
statistical analysis of drug trials any differently? It’s highly technical work.

Who should assume that responsibility? Why not the FDA? After
all, they alone see all the data. My specific proposal is for Congress to
mandate that the FDA analyze all clinical trials data strictly according to the
registered protocols and analysis plans. That requirement should apply to new
drugs or to approved drugs being tested for new indications. It should apply
also to publications reporting new trials of approved drugs. Corporations and investigators should be
prohibited from publishing their own in-house statistical analyses unless
verified by FDA oversight.

Why Bother?

There are three good reasons for prohibiting in-house corporate
analyses of clinical trials data. First, as the present example illustrates,
the inherent conflict of interest is simply too great to be ignored. Second, when
corporate statisticians who answer to marketing executives get “creative” in
the ways exposed here, then the conditions for valid statistical analyses no
longer apply – the statisticians are then on a fishing expedition and they are
no longer testing the defined study question with fidelity to the methods
specified in the IND protocol. In that case, any nominally significant statistical
findings are just exploratory, not actionable – not good enough to justify off-label
use of the drug, especially when properly evaluated alternatives are available.

Third, there can be no justification for treating the
production of influential publications in medical journals any differently than
we treat the production of potent drugs. Our FDA continuously inspects
production facilities for evidence of physical adulteration, even as far away
as China. They now need to monitor the adulteration of clinical trials reports
in medical journals. The harms of adulterated analyses can be just as serious
as the harms of adulterated products.

Push Back from
Pharma?

We can expect the pharmaceutical industry to mount a First
Amendment challenge to this proposal. It will fail, because the public health
is too important. Just as there is no First Amendment right to shout fire in a
crowded theater, so also corporations have no First Amendment right to say a
drug is safe and effective when they know it isn’t. That is a betrayal of
patients.

The corporations will also claim piously that their
publications undergo peer review. Sadly, that is no barrier to this pervasive corporate
bias because the peer reviewers for medical journals don’t see all the real
data – they see only the data the corporation wants them to see. Only the FDA sees
all the data. We can no longer cling to the myth of informed and unbiased peer
review of clinical trials reports. The corporations rely on that myth as a fig
leaf to support their First Amendment claims and to defend their practice of
in-house statistical analyses. Moreover, medical journals also are subject to
bias and conflict of interest. We could note that the Associate Editor of
American Journal of Psychiatry in 2004 was also a major U.S. key opinion leader
for Forest Laboratories. According to one of the released depositions, he was
instrumental in securing acceptance of the report by the journal.

Business as Usual?

The present example is not an isolated case. Dr. Jureidini
and his co-authors described several similar, recent examples. One of those was
the reanalysis by
Jureidini and others of an infamous
trial of paroxetine for pediatric depression. And still, fresh exposés keep
appearing. The latest is from Lisa Cosgrove at the University of Massachusetts
in Boston and her colleagues, involving “ghost management of the information
delivery process” for another new antidepressant drug, vortioxetine – available
on-line here.
(What is it with the antidepressants, anyway?) On this Health Care Renewal
blog, Roy Poses has called attention to these issues. As recently as June 8,
2016 he discussed
the Transparency International report on corruption in the pharmaceutical
sector.

Eric Topol, who helped
to expose the Vioxx scandal, made similar points recently in a BMJ commentary: “The bad science
in clinical trials has been well documented and includes selective publication
of positive results, data dredging, P hacking, HARKing, and changing the
outcomes that were prespecified at the beginning of the study….Furthermore, the disparity between what appears in peer
reviewed journals and what has been filed with regulatory agencies is long standing
and unacceptable.”

It’s No Time for Old
Solutions

As the eye-popping numbers
of children treated with escitalopram show, even off-label use of an
undistinguished drug in a niche population can be highly profitable. That is
why I am proposing that the statistical analysis of clinical trials data can no
longer be entrusted to pharmaceutical corporations, on account of their massive
inherent conflict of interest. Open access to patient level data, as well as pre-registration
of protocols and of data analysis plans, have been actively promoted for some
years now to clean up the corporate bias in clinical trials. These are positive
developments, but they will not close the disconnection highlighted just above
by Dr. Topol. The once idealistic world of clinical trials has changed irreversibly
in the past 30 years. As one observer has noted,
“… in the course of time the coordinated
actions of industry, government, and the biomedical research community have
degraded the basic rules of empirical science…” We would do well to
acknowledge this fact, and to recognize with Abramson and
Starfield that “The
first step is to give up the illusion that the primary purpose of modern
medical research is to improve Americans’ health most effectively and
efficiently. In our opinion, the primary purpose of commercially funded
clinical research is to maximize financial return on investment, not health.”

When corporations are
involved, there is no point in prolonging the myth of noble and dispassionate
clinical scientists searching for truth in clinical trials. It’s over. We would
do better to stop pretending that corporate articles in medical journals are
anything but marketing messages disguised with the fig leafs of coöpted
academic authors and of so-called peer review. The case study reported out by
Drs. John Jureidini, Jay Amsterdam, and Leemon McHenry shows us the real face
of business as usual in commercial clinical trials. That being the case, it
makes no sense to expect corporations and academic key opinion leaders suddenly
to reform their biased and conflicted behavior. Only a structural change from
the outside like I propose here has any chance of succeeding. The statistical
analysis of clinical trials is too important to be entrusted to the sponsoring
corporations.

It is time for Congress to
grasp this nettle. The time for enforcement discretion is past, and we need Congress
either to direct the FDA to act or to create a new mechanism of oversight. To
do nothing would be unthinkable.

Bernard J. Carroll

Professor and Chairman Emeritus,

Department of Psychiatry,

Duke University Medical Center.

E-mail: bcarroll40@comcast.net

The writer is a former chairman of the Psychopharmacologic
Drugs Advisory Committee, Food and Drug Administration, U.S Public Health
Service.

Acknowledgment: Several colleagues
commented and made suggestions on drafts of this post – in particular John M.
Nardo, MD, Donald F. Klein, M.D., and Patrick Skerrett from STAT News.

Update 06-23-2016: This post was cross-posted on Naked
Capitalism, where some interesting comments can be found.

9 comments:

Nobody takes the manufacturing corporation’s word for it concerning the safety and performance of X-ray machines or cardiac defibrillators.

This is horrendous but not surprising. Agree with the need for external, impartial oversight. On s personal note, several young relatives were adversely affected by such drugs in the late 1990s-early 2000s, with violent behavior and suicidal thoughts, that contributed to their needing acute psychiatric emergency care and having problems that persist to this day. At the time I was astonished by the suicidal ideation in my relative on a new antidepressant, xceptionally out of character, that I observed personally.

(As an aside, sadly, too many people take the manufacturing corporation’s "word for it" concerning the safety and performance of healthcare information technology.)

I increasingly believe my reputation for ruthless pursuit of the truth, already online about EHRs since the late 1990s, led to my being declared persona not grata in pharma. For instance, when I sought rehire in drug safety surveillance. After being sought by a department executive ca. 2005 who knew me, I was flat turned out of the office of his boss, a former FDA official, after a short visit - with the refrain that "we don't need medical informatics here." Post at http://hcrenewal.blogspot.com/2005/12/report-life-science-manufacturers.html.

I experienced similar, perplexing shunning by the Senior VP of a CRO I spoke with a decade ago (in that case, he said he "found nothing in my CV of value to a CRO").

Perhaps what they meant was "we don't need an honest medical informaticist here who can actually detect and who may blow the whistle on our activities."

I'm sorry to hear you felt it too Scot. It seems to have gotten worse over the years. To advance in today's corporate culture, honesty is not the best and living by the golden rule will get you laid off. It's one reason why older more life experienced workers have a hard time finding jobs.

There are some things I just won't do. Maybe that's a choice, and we have to live with our choices. I know my income has suffered because of it.

But doctors, you got yourselves into this corporate healthcare mess. Lead the way out. We consumers do not have the education, background, experience to fix this problem. You doctors do, and I think it's your responsibility to do so.

The outright mistruth fed to us every day on the TV, Internet, and elsewhere has stretched past the point of credulity.

Quite so. Perhaps I should have made it clear that I was thinking of the formation of groups representing patients in this context, independent of partisan interests. I fully appreciate that many existing groups David is referring to may have hidden financing and hidden agendas. I am sure there must be at least some existing groups that are not tied to pharmaceutical companies. With appropriate help and direction from the profession it would not be difficult to initiate a system whereby a small nucleus of such groups could be encouraged and expanded. I can see a mobile app here…

I agree about the Patient Union and independent data analysis. The other issue not mentioned is that we need to ban big pharma reps from becoming FDA regulators or vice versa for an extended period of time. Personally, I'd like to see a requirement of a percentage of laypeople or experts from related fields (like biochemistry professors or chemical engineers or others with sufficient science background to understand the issues) being part of any FDA panel, to assure there is some outside scrutiny of people who aren't already indoctrinated into "the way we do things" in the field.

Big Pharma corruption is rampant and very dangerous. It's definitely past time to do something major to stop this travesty masquerading as "science."

I taught an evidence-based pharmacotherapy course in pharmacy schools. i showed the students how to access FDA and VA monographs reviewing new drugs. Routinely, the students would find publications of results from the same trials in the review and other studies not included in the reviews. What was worse was when they found information on the drugs from their classroom presentations from clinical faculty that contradicted FDA reviews, and sometimes the origin of the slides presented to them by instructors came from "slide-decks" given to the professors by the companies. I could not get the students to believe the results of the FDA for themselves.

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